U.S. patent number 6,284,268 [Application Number 09/209,066] was granted by the patent office on 2001-09-04 for pharmaceutical compositions containing an omega-3 fatty acid oil.
This patent grant is currently assigned to Cyclosporine Therapeutics Limited. Invention is credited to Nuala Clarke, Awadhesh Mishra, Iskander Moussa, Zeibunissa Ramtoola.
United States Patent |
6,284,268 |
Mishra , et al. |
September 4, 2001 |
Pharmaceutical compositions containing an omega-3 fatty acid
oil
Abstract
Self-emulsifying microemulsion or emulsion preconcentrate
pharmaceutical compositions containing an omega-3 fatty acid oil
such as a fish oil and a poorly water soluble therapeutic agent
such as cyclosporin are formulated for administration, particularly
oral administration to a human. The preconcentrates, which are
substantially free of or contain only minor amounts of a
hydrophilic solvent system, contain a pharmaceutically effective
amount of an omega-3 fatty acid oil; a therapeutically effective
amount of a poorly water soluble therapeutic agent that is
substantially soluble in the omega-3 fatty acid oil; and a
surfactant system comprising at least one surfactant.
Microemulsions or emulsions formed by diluting the self-emulsifying
preconcentrate with an aqueous solution are also provided.
Inventors: |
Mishra; Awadhesh (Nuns Island,
CA), Moussa; Iskander (Montreal, CA),
Ramtoola; Zeibunissa (Dublin, IE), Clarke; Nuala
(Dublin, IE) |
Assignee: |
Cyclosporine Therapeutics
Limited (Dublin, IE)
|
Family
ID: |
26771075 |
Appl.
No.: |
09/209,066 |
Filed: |
December 10, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
988270 |
Dec 10, 1997 |
|
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|
Current U.S.
Class: |
424/455; 424/423;
514/786; 514/974; 514/937; 514/785; 424/443; 424/452; 424/456;
514/784; 424/451 |
Current CPC
Class: |
A61K
9/4858 (20130101); A61P 35/00 (20180101); A61P
33/02 (20180101); A61P 5/24 (20180101); A61P
31/10 (20180101); A61P 7/04 (20180101); A61P
31/12 (20180101); A61P 33/06 (20180101); A61P
3/10 (20180101); A61P 25/22 (20180101); A61P
13/02 (20180101); A61K 38/13 (20130101); A61P
37/08 (20180101); A61P 9/02 (20180101); A61P
25/20 (20180101); A61P 25/06 (20180101); A61P
1/04 (20180101); A61P 37/06 (20180101); A61P
31/04 (20180101); A61P 13/12 (20180101); A61P
7/02 (20180101); A61P 9/10 (20180101); A61K
31/216 (20130101); A61P 19/06 (20180101); A61P
21/02 (20180101); A61P 43/00 (20180101); A61P
29/00 (20180101); A61P 9/06 (20180101); A61P
5/14 (20180101); A61P 25/24 (20180101); A61P
39/00 (20180101); A61P 3/04 (20180101); A61P
3/06 (20180101); A61P 9/12 (20180101); A61P
9/00 (20180101); A61K 9/1075 (20130101); A61P
25/08 (20180101); A61K 38/13 (20130101); A61K
31/20 (20130101); A61K 38/13 (20130101); A61K
2300/00 (20130101); Y10S 514/974 (20130101); Y10S
514/937 (20130101) |
Current International
Class: |
A61K
9/48 (20060101); A61K 31/216 (20060101); A61K
31/21 (20060101); A61K 38/12 (20060101); A61K
38/13 (20060101); A61K 9/107 (20060101); A61K
009/10 (); A61K 009/107 (); A61K 009/48 (); A61K
009/66 () |
Field of
Search: |
;424/450,455,456,423,443,451,452 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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May 1989 |
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EP |
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0 589 843 A1 |
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EP |
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Mar 1997 |
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EP |
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EP |
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Dec 1999 |
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EP |
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GB |
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WO 94/08603 |
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WO |
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WO 94/08605 |
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WO |
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WO |
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WO 94/25068 |
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WO |
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WO |
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WO |
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WO |
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WO 97/00080 |
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WO |
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WO |
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WO 97/22358 |
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Jun 1997 |
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WO |
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WO 97/25977 |
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Jul 1997 |
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WO |
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WO 97/26003 |
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Jul 1997 |
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WO |
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WO 97/36610 |
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Oct 1997 |
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WO |
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Primary Examiner: Spear; James M.
Attorney, Agent or Firm: Dann, Dorfman, Herrell and Skillman
Eland; Stephen H.
Parent Case Text
This application claims priority from U.S. Provisional Application
60/084,516, filed May 7, 1998 and is a continuation-in-part of U.S.
application Ser. No. 08/988,270, filed Dec. 10, 1997, now
abandoned.
Claims
What is claimed is:
1. A self-emulsifying preconcentrate pharmaceutical composition
capable of forming an oil-in-water microemulsion or emulsion upon
dilution with an aqueous solution, comprising:
a) a pharmaceutically effective amount of an omega-3 fatty acid
oil;
b) a therapeutically effective amount of a poorly water soluble
therapeutic agent, wherein the poorly water soluble therapeutic
agent is substantially soluble in the omega-3 fatty acid oil;
and
c) a surfactant system comprising at least one surfactant; wherein
the composition contains minor amounts or is substantially free of
a hydrophilic solvent system.
2. The composition of claim 1, wherein the composition is a
microemulsion preconcentrate.
3. The composition of claim 1, wherein the composition is an
emulsion preconcentrate.
4. The composition of claim 1, wherein the composition is adapted
for oral administration.
5. The composition of claim 1, wherein the omega-3 fatty acid oil
is present in an amount ranging from 5 to 70% by weight.
6. The composition of claim 1, wherein the therapeutic agent is a
cyclosporin.
7. The composition of claim 1, wherein the omega-3 fatty acid oil
comprises an omega-3 fatty acid oil selected from the group
consisting of eicosapentaenoic acid, salts of eicosapentaenoic
acid, docosahexaenoic acid, salts of docosahexaenoic acid,
triglycerides of eicosapentaenoic acid, triglycerides of
docosahexaenoic acid, ethyl esters of eicosapentaenoic acid, ethyl
esters of docosahexaenoic acid and mixtures thereof.
8. The composition of claim 1, wherein the omega-3 fatty acid oil
comprises a component of a fish oil or a mixture of fish oils.
9. The composition of claim 8, wherein the omega-3 fatty acid
component of the fish oil or the mixture of fish oils is at least
50% by weight.
10. The composition of claim 8, wherein the omega-3 fatty acid
component of the fish oil or the mixture of fish oils is at least
70% by weight.
11. The composition of claim 8, wherein the omega-3 fatty acid
component of the fish oil or the mixture of fish oils is at least
80% by weight.
12. The composition of claim 1, wherein the omega-3 fatty acid oil
comprises omega-3 fatty acid triglycerides.
13. The composition of claim 1, wherein the omega-3 fatty acid oil
comprises omega-3 fatty acid ethyl esters.
14. The composition of claim 1, wherein the therapeutic agent is
selected from the group consisting of an analgesic, anti-allergic
agent, anti-fungal, anti-inflammatory agent, anti-arrythmic agent,
antibiotic, anticoagulant, antidepressant, antidiabetic agent,
anti-epilepsy agent, antihypertensive agent, anti-gout agent,
anti-malarial, anti-migraine agent, antimuscarinic agent,
antineoplastic agent, anti-protozoal agent, anxiolytic, thyroid,
anti-thyroid, antiviral, anoretic, bisphosphonate, cardiac
inotropic agent, cardiovascular agent, corticosteroid, diuretic,
dopaminergic agent, gastrointestinal agent, hemostatic, histamin
receptor antagonist, hypnotic, immunosuppressant, kidney protective
agent, lipid regulating agent, muscle relaxant, neuroleptic,
neurotropic agent, opioid agonist and antagonist,
parasympathomimetic, protease inhibitor, prostglandin, sedative,
sex hormone, stimulant, sympathomimetic, vasodilator and xanthin or
mixtures thereof.
15. The composition of claim 1, wherein the composition is adapted
for topical administration.
16. The composition of claim 1, wherein the composition is adapted
for parenteral administration.
17. A microemulsion or emulsion pharmaceutical composition
comprising the self-emulsifying preconcentrate of claim 1 diluted
with an aqueous solution.
18. The composition of claim 17, wherein the composition is a
microemulsion.
19. The composition of claim 17, wherein the composition is an
emulsion.
20. The composition of claim 17, wherein the composition is adapted
for oral administration.
21. The composition of claim 17, wherein the therapeutic agent is a
cyclosporin.
22. The composition of claim 17, wherein the omega-3 fatty acid oil
comprises an omega-3 fatty acid oil selected from the group
consisting of eicosapentaenoic acid, salts of eicosapentaenoic
acid, docosahexaenoic acid, salts of docosahexaenoic acid,
triglycerides of eicosapentaenoic acid, triglycerides of
docosahexaenoic acid, ethyl esters of eicosapentaenoic acid, ethyl
esters of docosahexaenoic acid and mixtures thereof.
23. The composition of claim 17, wherein the omega-3 fatty acid oil
comprises a component of a fish oil or a mixture of fish oils.
24. The composition of claim 23, wherein the omega-3 fatty acid
component of the fish oil or the mixture of fish oils is at least
50% by weight.
25. The composition of claim 23, wherein the omega-3 fatty acid
component of the fish oil or the mixture of fish oils is at least
70% by weight.
26. The composition of claim 23, wherein the omega-3 fatty acid
component of the fish oil or the mixture of fish oils is at least
80% by weight.
27. The composition of claim 17, wherein the therapeutic agent is
selected from the group consisting of an analgesic, anti-allergic
agent, anti-fungal, anti-inflammatory agent, anti-arrythmic agent,
antibiotic, anticoagulant, antidepressant, antidiabetic agent,
anti-epilepsy agent, antihypertensive agent, anti-gout agent,
anti-malarial, anti-migraine agent, antimuscarinic agent,
antineoplastic agent, anti-protozoal agent, anxiolytic, thyroid,
anti-thyroid, antiviral, anoretic, bisphosphonate, cardiac
inotropic agent, cardiovascular agent, corticosteroid, diuretic,
dopaminergic agent, gastrointestinal agent, hemostatic, histamine
receptor antagonist, hypnotic, immunosuppressant, kidney protective
agent, lipid regulating agent, muscle relaxant, neuroleptic,
neurotropic agent, opioid agonist and antagonist,
parasympathomimetic, protease inhibitor, prostglandin, sedative,
sex hormone, stimulant, sympathomimetic, vasodilator and xanthin or
mixtures thereof.
28. The composition of claim 17, wherein the omega-3 fatty acid oil
comprises omega-3 fatty acid triglycerides.
29. The composition of claim 17, wherein the omega-3 fatty acid oil
comprises omega-3 fatty acid ethyl esters.
30. The composition of claim 17, wherein the composition is adapted
for topical administration.
31. The composition of claim 17, wherein the composition is adapted
for parenteral administration.
32. The composition of claim 17, wherein the amount of aqueous
solution to preconcentrate is 1:1 or greater.
33. A method of lowering the therapeutically effective amount of a
poorly water soluble therapeutic agent comprising administering to
a human in need of a therapeutically effective amount of the
therapeutic agent the self-emulsifying preconcentrate of claim 1,
wherein the omega-3 fatty acid oil exerts an additive effect or
synergistic effect to the therapeutic effect of the therapeutic
agent.
34. A method of reducing the side effects of a poorly water soluble
therapeutic agent comprising administering to a human in need of a
therapeutically effective amount of the therapeutic agent the
self-emulsifying preconcentrate of claim 1, wherein the omega-3
fatty acid oil mediates at least one negative side effect of the
therapeutic agent.
35. A method of lowering the therapeutically effective amount of a
poorly water soluble therapeutic agent comprising administering to
a human in need of a therapeutically effective amount of the
therapeutic agent the microemulsion or emulsion of claim 17,
wherein the omega-3 fatty acid oil exerts an additive effect or
synergistic effect to the therapeutic effect of the therapeutic
agent.
36. A method of reducing the side effects of a poorly water soluble
therapeutic agent comprising administering to a human in need of a
therapeutically effective amount of the therapeutic agent the
microemulsion or emulsion of claim 17, wherein the omega-3 fatty
acid oil mediates at least one negative side effect of the
therapeutic agent.
37. The method according to any of claims 33, 34, 35 or 36, wherein
the poorly water soluble therapeutic agent is a cyclosporin.
38. A hard or softgel capsule formulation comprising the
composition of claim 1.
39. A self-emulsifying preconcentrate pharmaceutical composition
capable of forming an oil-in-water microemulsion or emulsion upon
dilution with an aqueous solution, comprising:
a) a pharmaceutically effective amount of an omega-3 fatty acid
oil;
b) a therapeutically effective amount of a poorly water soluble
therapeutic agent, wherein the poorly water soluble therapeutic
agent is substantially soluble in the omega-3 fatty acid oil;
and
c) a surfactant system comprising at least one surfactant.
Description
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions
containing an omega-3 fatty acid oil and a therapeutic agent. In
particular, the present invention relates to the administration,
particularly oral, of self-emulsifying microemulsion and emulsion
preconcentrate formulations or microemulsions and emulsions which
contain omega-3 fatty acid oil and a poorly water soluble
therapeutic agent, for example, cyclosporin. Preferably, the
omega-3 fatty acid oil and therapeutic agent exert an additive or
synergistic therapeutic effect or the omega-3 fatty acid oil
mediates the negative side effects of the therapeutic agent.
BACKGROUND OF THE INVENTION
Omega-3 fatty acid oils possess properties that can be used for
numerous therapeutic advantages, including treatment of autoimmune
and inflammatory diseases such as rheumatoid arthritis, psoriasis,
inflammatory bowel diseases such as Crohn's disease and ulcerative
colitis; immunosuppressive treatment; hypertension prophylaxis in
normal humans and in heart transplant patients; coronary heart
disease; hyperlipidemia; hypertriglyceridemia; improvement of renal
function and nephrotoxicity reduction. U.S. Pat. No. 4,678,808
describes the use of these oils to treat disorders associated with
arachidonic acid metabolites, including autoimmune syndromes, acute
and chronic inflammatory diseases, atherosclerosis, stroke,
myocardial infarction, deep vein thrombosis, surgery,
hyperlipidaemic states, hypertension, enhanced platelet
responsiveness, vascular lesions and occlusions, vascular spasm and
diabetes. According to U.S. Pat. No. 5,225,441, which describes
compositions for treating gingivitis and periodontitis, omega-3
polyunsaturated fatty acids compete with omega-6 polyunsaturated
fatty acids as a substrate in the arachidonic acid cascade and can
therefore alter the synthesis of prostaglandin and leukotrienes,
both of which are powerful mediators of inflammation and immune
response. Other uses of omega-3 fatty acid oils are described in
U.S. Pat. No. 5,034,415 (diabetes mellitus), U.S. Pat. No.
4,843,095 (rheumatoid, arthritis), JP 2253629 (anticancer), U.S.
Pat. No. 4,879,312 (enhancing angiogenesis), JP 1290625
(improvement of cerebral function), EP 378,824 (anti-cachexia,
cholesterol and triglyceride levels reduction, platelet aggregation
inhibition, colon adenocarcinomas growth inhibition), U.S. Pat. No.
5,457,130 (cancer cachexia, malignant tumors, abnormal cAMP levels
in adipose tissue, lipolytic activity inhibition) and U.S. Pat. No.
5,436,269 (hepatitis).
Cyclosporins are an example of a class of drugs that is soluble in
omega-3 fatty acid oil and capable of exerting an additive or
synergistic therapeutic effect with the omega-3 fatty acid oil.
Alternatively, the omega-3 fatty acid oil mediates the negative
side effects, such as nephrotoxicity, of a cyclosporin such as
cyclosporin A.
Cyclosporin A (CyA) is a lipophilic cyclic undecapeptide that can
be isolated from the fungus Tolypoclodium inflatum Gams and which
produces calcium dependent, specific and reversible inhibition of
transcription of interleukin-2 and several other cytokines, most
notably in T helper lymphocytes. Because of its immunosuppressive
properties, it is widely used as first line therapy in the
prophylaxis and treatment of transplant rejection (e.g., allo- or
xeno-transplant rejection such as in patients receiving heart,
lung, combined heart-lung, liver, kidney, pancreatic, skin or
corneal transplants) and various autoimmune and inflammatory
diseases. CyA is used in the treatment of multi-drug resistance
syndrome, for example in patients undergoing chemotherapy or
following organ transplantations. In patients with severe disease
refractory to standard treatment; CyA is an effective therapy in
acute ocular Behcet's syndrome; endogenous uveitis; psoriasis;
atopic dermatitis; arthritis, particularly rheumatoid arthritis;
active Crohn's disease and nephrotic syndrome. Other conditions
include arthritis chronica progrediente and arthritis deformans,
autoimmune hematological disorders including hemolytic anemia,
aplastic anemia, pure red-cell anemia and idiopathic
thrombocytopenia, systemic lupus erythematosus, polychondroitis,
scleroderma, Wegener granulamtosis, dermatomyositis, chronic active
hepatitis, myasthenia gravis, Steven-John syndrome, idiopathic
sprue, autoimmune inflammatory bowel disease, e.g., ulcerative
colitis, endocrine ophthalmology, Graves disease, sarcoidosis,
multiple sclerosis, primary biliary cirrhosis, juvenile diabetes,
keratoconjunctivitis sicca and vernal keratoconjunctivitis,
interstitial lung fibrosis, psoriatic arthritis,
glomerulonephritis, juvenile dermatitis, asthma, tumors,
hyperproliferative skin disorders and fungal infections. This drug
has also been used to treat patients with moderate or severe
aplastic anemia who are ineligible for bone marrow transplantation
and those with primary biliary cirrhosis. CyA may be effective in
patients with intractable pyoderma gangrenosum,
polymyositis/dermatomyositis or severe, corticosteroid-dependent
asthma. CyA is known to have a very specific effect on T-cell
proliferation although the precise mechanism remains unclear. A
number of non-immunosuppressive analogues of cyclosporin A have
been shown to have resistance modifier activity and some are more
potent than the parent compound. Nephrotoxicity, hepatotoxicity,
hypertension, headache, hypertrichosis, gingival hyperplasia,
neurological and gastrointestinal effects, thrombocytopenia and
microangiopathic hemolytic anemia, hyperkalemia and hyperuricemia
and development of skin and lymphoproliferative malignancies are
the most common adverse events in cyclosporin recipients.
CyA and fish oils have been administered concurrently to organ
transplant patients in various clinical trials. For instance,
Andreassen et al. (JAAC, 29(6): 1324-31 (1997) reported effective
hypertention prophylaxis in heart transplant patients who were
given cyclosporin A and 4 g of fish oil. Cyclosporin A-treated and
fish oil fed renal transplant recipients had improved renal
function following a rejection episode (Transplantation, 54:257
(1992)). U.S. Pat. No. 5,118,493 describes the administration of
CyA together with an omega-3 fatty acid oil to mediate the
nephrotoxic effects of the cyclosporin.
Certain oil mixtures of lipophilic drugs such as a cyclosporin with
vegetable oils or other lipidic substances, surface active agents,
solvents and other excipients are known to spontaneously produce
dispersions of very low mean particle size (such as<200 nm) when
mixed with an aqueous medium. These dispersions are known as
microemulsions and the oily mixtures that produce the
microemulsions are popularly referred to as microemulsion
preconcentrates. Upon oral delivery, the microemulsion
preconcentrates are thought to produce similar dispersions of very
low particle size with gastric and other physiological fluids.
Cyclosporins are highly lipophilic, poorly water soluble and,
therefore, have been supplied as an olive oil or peanut oil
solution for clinical use. However, the bioavailability of
cyclosporin from such oily solutions is very low and gives rise to
great intersubject variation with reported systemic availability
ranging from 4 to 25% (Takada, K. et al, J. Pharmacobio-Dyn.,
11:80-7 (1988)). The bioavailability of cyclosporin has been
reported to be dependent on food, bile and other interacting
factors (Clin. Pharmacokinetics, 24:472-95 (1993)). A widely used
commercial formulation of CyA, SANDIMMUNE.RTM. for oral
administration, is a solution of cyclosporin A in vegetable oil
derivatives containing some other inactive excipients. Very high
inter- and intra-patient and food dependent variability in the
bioavailability of CyA has been observed from this formulation. The
commercial microemulsion preconcentrate formulation, NEORAL.RTM.,
has been claimed to provide high bioavailability for CyA with low
inter-and intra-patient variability. However, risks of adverse drug
reactions have been indicated on switching to Neoral.RTM. (see,
e.g., Drug Saf, 16:366-73 (1996); Lancet, 348:205 (1996)).
Numerous microemulsion preconcentrate formulations are known,
including soft gel formulations, for enhancing the solubilization
and oral bioavailability of a poorly water soluble drug compound
such as cyclosporine. Typically, these formulations include an
active agent, an oil component, a surfactant to emulsify the
formulation and a hydrophilic solvent/co-surfactant system to
solubilize the active agent. Typical solvent/co-surfactant systems
include ethanol, polyethylene glycols, propylene carbonate,
dimethylisosorbide, Transcutol and/or Glycofurol. Disadvantages of
these formulations include stability or precipitation problems
caused by migration of volatile hydrophilic solvents or cosolvents
(e.g., ethanol can permeate a gelatin shell at normal storage
temperatures), stability or precipitation problems caused by
hygroscopic solvents or co-surfactants (e.g., propylene glycols,
Transcutol, Glycofurol), and toxicity problems caused by addition
of certain solvents or co-surfactants (e.g.,
dimethylisosorbide).
Typically, the oil component of a conventional microemulsion
consists of fatty acid mono-, di- or triglycerides from a vegetable
oil; medium chain triglycerides and/or mono- or di-glycerides;
mixtures of glycerides and polygycolized glycerides; tocol,
tocopherols, and/or tocotrienols; or hydrophobic alcohols. U.S.
Pat. No. 5,603,951 describes a microemulsion concentrate containing
cyclosporin as an active ingredient, dimethylisosorbide as a
required co-surfactant, a surfactant, and an oil which can be
refined fish oil, these components being present in the ratio of
1:1-5:2-10:1-5. The inventors of the '951 patent added
dimethylisosorbide, which is a solvent available under the
Tradename ARLASOVE.RTM., to the formulation to address the
disadvantages listed above for prior solvents/co-surfactants
systems such as ethanol, Transcutol, or Glycofurol. The '951
preconcentrates are formed by dissolving the cyclosporin in the
dimethylisosorbide at a temperature of approximately 60.degree. C.
followed by addition of the oil component and the surfactant.
It is an object of the present invention to provide a stable,
self-emulsifying microemulsion or emulsion preconcentrate
formulation and/or a microemulsion or emulsion containing an
omega-3 fatty acid oil that is capable of enhancing the
bioavailability of a poorly water soluble therapeutic agent while
minimizing the inter- and intra-patient or food variability in the
bioavailability of the therapeutic agent. A further object is to
provide self-emulsifying preconcentrates or corresponding
microemulsions and emulsions having increased therapeutic agent
dosing reproducibility compared to conventional formulations. An
additional object is to provide self-emulsifying preconcentrates or
corresponding microemulsions or emulsions containing an omega-3
fatty acid oil and a poorly water soluble therapeutic agent in
which the bioavailability and dosing reproducibility of both the
omega-3 fatty acid oil and the therapeutic agent is high.
It is an additional object of this invention to provide a stable
self-emulsifying microemulsion or emulsion preconcentrate
formulation and/or a microemulsion or emulsion in which the omega-3
fatty acid oil and the therapeutic agent exert an additive or
synergistic therapeutic effect or the omega-3 fatty acid oil
mediates the negative side effects of the therapeutic agent.
A further object of this invention is to provide a stable
self-emulsifying preconcentrates and/or a microemulsion or emulsion
in which the poorly water soluble therapeutic agent is
substantially soluble in the omega-3 fatty acid oil, thus
eliminating or drastically reducing the need for substantial
amounts of a hydrophilic solvent system.
A further object of this invention is to provide a stable
self-emulsifying microemulsion or emulsion preconcentrate
formulation and/or a microemulsion or emulsion containing an
omega-3 fatty acid oil and a poorly water soluble therapeutic agent
which is suitable for formulation into soft or hard capsules for
oral administration.
A still further object of this invention is to provide a stable
self-emulsifying microemulsion or emulsion preconcentrate soft or
hard capsule formulation containing an omega-3 fatty acid oil and a
poorly water soluble therapeutic agent having relatively high
therapeutic amounts of both the omega-3 fatty acid oil and the
poorly water soluble therapeutic agent.
SUMMARY OF THE INVENTION
Surprisingly, it has been found that stable, self-emulsifying
microemulsion or emulsion preconcentrates comprising a poorly water
soluble drug can be formed using an omega-3 fatty acid oil to
substantially solubilize the poorly water soluble drug. The
solubilizing properties of the omega-3 fatty acid oil eliminate or
drastically reduce the need for substantial amounts of a
hydrophilic solvent/co-solvent system, also allowing for
formulation of preconcentrates that are substantially free of a
hydrophilic solvent/co-solvent system or contain only minor amounts
of a hydrophilic solvent/co-solvent system. It was also found that
the solubility of a poorly water soluble drug was enhanced in oils
containing a mixture of omega-3 fatty acid oils, thus allowing
formulation of preconcentrates containing relatively higher
quantities of the poorly water soluble drug. The self-emulsifying
microemulsion and emulsion preconcentrates according to the instant
invention take the form of a poorly water soluble therapeutic agent
substantially solubilized in an omega-3 fatty acid oil that is
capable of being self-emulsified by a surfactant system comprising
at least one surfactant when the preconcentrate is diluted with an
aqueous medium.
Thus, the present invention provides a self-emulsifying
preconcentrate pharmaceutical composition suitable for
administration to a mammal, particularly oral administration to a
human, and capable of forming an oil-in-water microemulsion or
emulsion upon dilution with an aqueous solution, comprising
(a) a pharmaceutically effective amount of an omega-3 fatty acid
oil;
(b) a therapeutically effective amount of a poorly water soluble
therapeutic agent, wherein the poorly water soluble therapeutic
agent is substantially soluble in the omega-3 fatty acid oil;
and
(c) a surfactant system comprising at least one surfactant;
wherein the composition contains minor amounts or is substantially
free of a hydrophilic solvent system. The present invention also
provides microemulsions or emulsions formed by diluting a
self-emulsifying preconcentrate with an aqueous solution.
Compositions according to this invention that are substantially
free or contain only minor amounts of a hydrophilic solvent system
avoid the disadvantages of the prior art systems given above.
The therapeutic agent, which is substantially soluble in the
omega-3 fatty acid oil, is beneficially co-administered with the
omega-3 fatty acid oil to achieve, for instance, greater
bioavailability or less variation in the bioavailability of the
therapeutic agent, an additive therapeutic effect with the omega-3
fatty acid oil, a synergistic therapeutic effect with the omega-3
fatty acid oil, or a reduction in at least one side effect of the
therapeutic agent. Thus, the present invention also encompasses
methods for lowering the therapeutically effective amount of a
poorly water soluble therapeutic agent by administering to a human
in need of a therapeutically effective amount of the therapeutic
agent the self-emulsifying preconcentrates or the
microemulsions/emulsions of the present invention. Further, the
present invention encompasses methods for reducing the side effects
of a poorly water soluble therapeutic agent by administering to a
human in need of a therapeutically effective amount of the
therapeutic agent the self-emulsifying preconcentrates or the
microemulsions/emulsion of the present invention.
A preferred therapeutic agent is a cyclosporin, particularly
cyclosporin A. Preferred omega-3 fatty acid oils include omega-3
free fatty acids, omega-3 fatty acid triglycerides and omega-3
fatty acid ethyl esters, such as EPA, DHA, triglycerides of EPA,
triglycerides of DHA, ethyl esters of EPA, ethyl esters of DHA and
mixtures thereof.
Oils containing high concentrations of omega-3 fatty acid oils such
as fish oils or their mixtures are particularly useful for forming
self-emulsifying preconcentrates, microemulsions or emulsions
according to the present invention. Preferably, the oil is fish oil
containing at least 50%, preferably at least 70%, more preferably
at least 80% omega-3 fatty acid oil to obtain a pharmaceutically
effective amount of an omega-3 fatty acid oil in a minimal volume.
Because of the solubility of the therapeutic agent in the oil or
mixture of oils containing omega-3 fatty acid oil, self-emulsifying
preconcentrate, microemulsion or emulsion compositions containing
both a therapeutically effective amount of the therapeutic agent
and an amount of omega-3 fatty acid oil needed to achieve
beneficial co-administration with the therapeutic agent can be
formulated with minimal added excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a pseudo-ternary phase diagram for the placebo system
described in Example 8 upon a 1 to 20 dilution of the
preconcentrate with water. The diagram plots the relative
concentration of Labrasol (0 to 100%), the concentration of the
omega-3 fatty acid oil K85TG (0 to 100%), and the concentration of
Cremophor RH40: Tween 80 in a 2:1 ratio (0 to 100%) for the placebo
system. The relative concentration of Labrasol increases from 0% at
the lower right hand margin of the diagram to 100% at the lower
left corner; the relative concentration of Cremophor RH40: Tween 80
in a 2:1 ratio increases from 0% at the baseline of the diagram to
100% at the apex; and the relative concentration of K85TG increases
from 0% at the apex to 100% at the lower right hand corner of the
diagram. The shaded area identifies those compositions having C1,
C1/C2 or C2 clarity as the microemulsion region for a 1 to 20
dilution of the preconcentrate with water; and
FIG. 2 shows a pseudo-ternary phase diagram for the 100 mg CyA
system described in Example 8 upon a 1 to 20 dilution of the
preconcentrate with water. The diagram plots the relative
concentration of Labrasol (0 to 100%), the concentration of the
omega-3 fatty acid oil K85TG (0 to 100%), and the concentration of
Cremophor RH40: Tween 80 in a 2:1 ratio (0 to 100%) for
compositions containing 100 mg CyA. The relative concentration of
Labrasol increases from 0% at the lower right hand margin of the
diagram to 100% at the lower left corner; the relative
concentration of Cremophor RH40: Tween 80 in a 2:1 ratio increases
from 0% at the baseline of the diagram to 100% at the apex; and the
relative concentration of K85TG increases from 0% at the apex to
100% at the lower right hand corner of the diagram. The shaded area
identifies those compositions having C1, C1/C2 or C2 clarity as the
microemulsion region for a 1 to 20 dilution of the preconcentrate
with water.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "omega-3 fatty acid oil" means a natural
or synthetic omega-3 fatty acid, and pharmaceutically acceptable
esters, derivatives, precursors or salts thereof and mixtures
thereof. Examples of omega-3 fatty acid oils include but are not
limited to omega-3 polyunsaturated, long-chain fatty acids such as
a eicosapenta-5,8,11,14,17-enoic acid (hereinafter "EPA"),
docosahexa-4,7,10,13,16,19-enoic acid (hereinafter "DHA"), and
.alpha.-linolenic acid; esters of an omega-3 fatty acid with
glycerol such as mono-, di- and triglycerides; esters of the
omega-3 fatty acid and a primary alcohol such as fatty acid methyl
esters and fatty acid ethyl esters; precursors of an omega-3 fatty
acid oil, such as EPA and DHA precursor .alpha.-linolenic acid; and
derivatives such as polyglycolized derivatives or polyoxyethylene
derivatives. Preferred omega-3 fatty acid oils are EPA or DHA,
triglycerides thereof, ethyl esters thereof and mixtures thereof.
The omega-3 fatty acids or their esters, derivatives, precursors,
salts and mixtures thereof can be used either in their pure form or
as a component of an oil such as fish oil (otherwise known as
marine oil), preferably highly purified fish oil concentrates, or
perilla oil or marine microalgae oil. Suitable fish oils are, for
example, those types which are recovered in substantial quantities
from cold-water fish, such as pilchard oil, menhaden oil, Peruvian
fish oil, sardine oil, salmon oil, herring oil, and mackerel oil.
Preferably, the fish oil has a high omega-3 fatty acid oil content,
such as 50% or higher, more preferably, 70% or higher, most
preferably 80% or higher. Examples of suitable omega-3 fatty acid
oils include the following oils available from Croda Oleochemicals
(England): Incromega TG3525 (35:25 EPA:DHA ratio; triglycerides),
Incromega E5015 (50:15 EPA:DHA ratio; ethyl esters) and the
following oils available from Pronova Biocare (Sandefjord, Norway):
EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE
and EPAX7010EE (further details listed in Table 1 herein).
Preferred mixtures include mixtures of fatty acid ethyl esters and
fatty acids; fatty acid ethyl esters and fatty acid triglycerides;
fatty acids and fatty acid triglycerides; and fatty acid esters,
fatty acid triglycerides and fatty acids such as mixtures
containing K85EE and EPAX6000FA; EPAX5000TG and EPAX6000FA; K85EE
and EPAX5000TG; and K85EE, EPAX6000FA and EPAX5000TG.
As used herein, the term "therapeutic agent" means a poorly water
soluble drug or a mixture of poorly water soluble drugs that can be
beneficially co-administered with an omega-3 fatty acid oil to a
mammal, especially a human. By "poorly water soluble drug" is meant
a drug that is insoluble in water or has an aqueous solubility of
less than about 5 part per 1000 parts of water by weight at
20.degree. C. Examples of beneficial co-administration include
co-administration that results in at least one synergistic
therapeutic effect or at least one additive therapeutic effect
between the therapeutic agent and the omega-3 fatty acid oil;
co-administration in which the omega-3 fatty acid oil mediates at
least one negative side effect of the therapeutic agent and
co-administration in which the omega-3 fatty acid oil solubilizes
the therapeutic agent to allow for greater bioavailability and/or
reduced variation in the bioavailability of the therapeutic agent.
For instance, in addition to other beneficial co-administration
effects, omega-3 fatty acid oil reduces the nephrotoxicity of
cyclosporin when co-administered, allowing treatment with higher
levels of cyclosporin and producing a greater clinical response at
a given dose of cyclosporin.
Examples of therapeutic agents include nephrotoxic drugs such as
cyclosporins and amphotericin B; cardiotoxic drugs such as
amphotericin B and FK506; drugs with immunosuppressive effects or
anti-inflammatory drugs such as drugs for treating rheumatology,
arthritis, psoriasis, inflammatory bowel disease, Crohn's disease
or demyelinating diseases including multiple sclerosis; anti-tumor
drugs such as melphalan, chlormethine, extramustinephosphate,
uramustine, ifosfamide, mannomustine, trifosfamide, streptozotocin,
mitobronitol, methotrexate, fluorouracil, cytarabine, tegafur,
idoxide, taxol, paclitaxel, daunomycin, daunorubicin, bleomycin,
amphotericin; hyperlipidemia or hypercholestolemia drugs such as
fenofibrate; dioplar disease drugs; drugs which increase lipids
and/or triglyceride levels; and drugs for treating Alzheimer's
disease. The therapeutic agent can be selected from a variety of
known classes of drugs including, but not limited to, analgesics,
anti-allergic agents, anti-fungals, anti-inflammatory agents,
anti-arrythmic agents, antibiotics, anticoagulants,
antidepressants, antidiabetic agents, anti-epilepsy agents,
antihypertensive agents, anti-gout agents, anti-malarials,
anti-migraine agents, antimuscarinic agents, antineoplastic agents,
anti-protozoal agents, anxiolytics, thyroids, anti-thyroids,
antivirals, anoretics, bisphosphonates, cardiac inotropic agents,
cardiovascular agents, corticosteroids, diuretics, dopaminergic
agents, gastrointestinal agents, hemostatics, histamine receptor
antagonists, hypnotics, immunosuppressants, kidney protective
agents, lipid regulating agents, muscle relaxants, neuroleptics,
neurotropic agents, opioid agonists and antagonists,
parasympathomimetics, protease inhibitors, prostglandins,
sedatives, sex hormones, stimulants, sympathomimetics, vasodilators
and xanthins. The therapeutic agent may comprise a mixture of
poorly water-soluble drugs that can be beneficially co-administered
with an omega-3 fatty acid oil.
As used herein, the term "a pharmaceutically effective amount of an
omega-3 fatty acid oil" means an amount effective either 1) to
solubilize a therapeutically effective unit dose amount of the
poorly water soluble therapeutic agent; 2) to exert an additive
therapeutic effect in combination with the poorly water soluble
therapeutic agent; 3) to exert a synergistic therapeutic effect in
combination with the poorly water soluble therapeutic agent; or 4)
to mediate, such as decrease, at least one negative side effect of
the therapeutic agent. Typically, the amount of omega-3 fatty acid
oil in a unit dose of the self-emulsifying microemulsion or
emulsion preconcentrate and/or microemulsion or emulsion can be
adjusted so that the daily dose of the omega-3 fatty acid oil is
from about 1.0 g to about 6.0 g in humans per day, preferably from
about 2.0 g to about 5.0 g, most preferably about 2.5 g to about
4.0 g per day. Alternatively, the typical dosage of the omega-3
fatty acid oil ranges from about 14 to 86 mg/kg/day; the typical
dosage of a fish oil contains an equivalent amount of omega-3 fatty
acid oil. Preferably, the unit dose amount for an oil containing
the omega-3 fatty acid oil ranges from about 5% to 70% of the
microemulsion or emulsion preconcentrate.
As used herein, the term "surfactant" means a non-ionic or ionic
surfactant having an HLB less than about 20. Suitable surfactants
include but are not limited to polyoxyethylene glycolated natural
or hydrogenated vegetable oils; polyoxyethylene sorbitan fatty acid
esters; polyoxyethylene fatty acid esters; polyoxyethylene alkyl
ethers; polyethylene glycol mono- and di- fatty acid esters;
transesterification product of natural vegetable oil triglyceride
with polyalkylene polyol; and fatty alcohol ethoxylates. Examples
of suitable surfactants include Cremophor-RH40, Cremophor-RH60,
Cremophor-EL, Tween-20, Tween-40, Tween-60, Tween-65, Tween-80,
Tween-85, Labrasol, Nikkol HCO-50, Nikkol HCO-40, Nikkol HCO-60,
Brij 30, Gelucire 44/14, Gycerox 767, lmwitor 742, lmwitor 308,
lmwitor 375, Labrafac Lipophile, Labrafac CM10, Tagat TO, Myrj 52,
Myvacet 9-45, and Vitamin E-TPGS.
As used herein, the term "substantially soluble" in reference to
the solubility of the poorly water soluble therapeutic agent in the
omega-3 fatty acid oil means the poorly water soluble therapeutic
agent is soluble in the omega-3 fatty acid oil or has a solubility
of more than 1 part per 100 parts of omega-3 fatty acid oil by
weight at 20.degree. C.
As used herein, the term "hydrophilic solvent system" means a
system comprising a solvent or co-solvent (other than an omega-3
fatty acid oil) with respect to the poorly water soluble
therapeutic agent and/or a co-surfactant having an HLB greater than
about 20. Example hydrophilic solvent system components include
ethanol, alkylene glycols such as propylene glycol, polyethylene
glycol, polyoxypropylene block copolymers, Glycofurol, Transcutol,
dimethylisosorbide and mixtures thereof. Preferred hydrophilic
solvent system components are 1,2-propylene glycol, ethanol and
polyethylene glycol having an average molecular weight of less than
or equal to 1000, individually or in combination. More preferred
hydrophilic solvent system components are 1,2-propylene glycol and
ethanol, individually or in combination. As used herein, the term
"minor amounts" as used in reference to a hydrophilic solvent
system means an amount less than about 10% by weight of the
components present in the preconcentrate, preferably less than
about 5% by weight, most preferably less than the amount of
therapeutic agent present in the formulation.
The self-emulsifying microemulsion and emulsion preconcentrate and
microemulsion and emulsion formulations according to the present
invention may optionally include minor amounts of a hydrophilic
solvent system to increase the shelf life or stability of the
preconcentrates. Other additives, such as antioxidants or
preservatives, may also be present. Examples include tocopherol,
tocopherols excipient, ascorbyl palmitate, butylated hydroxyanisol
or other antioxidants and preservatives listed in USP XXII,
Pharmaceutic Ingredients.
The self-emulsifying preconcentrates and the microemulsions and
emulsions of the instant invention can be adapted for oral
administration. Preferred oral dosage forms for the preconcentrates
include hard and softgel capsules. Preformed microemulsions and
emulsions are preferred oral dosage forms for the microemulsions
and emulsions. The formulations according to the instant invention
can also be administered by other routes of administration,
including topical administration or parenteral administration such
as i.v. or i.p. administration.
EXAMPLE 1
Solubility of Cyclosporin in Fish Oils at Ambient Temperature
The solubility at ambient temperature for cyclosporin A (CyA) was
determined at ambient temperature for fish oils containing
polyunsaturated omega-3 free fatty acid oil as free fatty acids
(EPAX6000FA), omega-3 fatty acid glycerides (EPAX5000TG,
EPAX4510TG, EPAX2050TG, and K85TG), omega-3 fatty acid ethyl esters
(K85EE, EPAX7010OEE and K80EE) and in a mixture of free fatty acids
and ethyl esters (EPAX6000FA/K85EE) (Pronova Biocare, Sandefjord,
Norway). The K85TG is a mixed glyceride form obtained by
transesterification of K85EE with glycerol giving the resulting
blend: K85 monoglyceride: 5-15%; K85 diglyceride: 20-30%; K85
triglyceride: 50-70% and K85EE remnants:<5%. Further details
regarding these omega-3 fatty acid oils and the CyA solubilities
are given in Table 1.
The solubility of CyA in various oils was found to be variable. A
blend of K85EE with EPAX6000FA increased the solubilizing power for
CyA greatly compared to either omega-3 fatty acid oil by itself.
Furthermore, this CyA solution in a mixture of K85EE and EPAX 6000
remained in the form of a clear solution at low and high
temperatures, such as 2-8.degree. C. and about 40.degree. C. No
precipitation or crystallization occurred upon cooling to
about-20.degree. C. for more than 24 hours. Thus, these initial
findings indicate that CyA microemulsion preconcentrates made with
this fish oil blend might have very good thermal stability over a
wide temperature range.
TABLE 1 .omega.-3 EPA to Solubility Chemical content DHA Additives
mg CyA per Fish Oil Form % EPA % DHA % ratio mg/g g solvent
EPAX6000FA free fatty 55-60 33 22 3:2 Vit A: 1 IU 557 mg/g acid Vit
D: 1 IU Vit E: 3-4.5 EPAX5000TG glycerides 50 30 20 3:2 Vit E:
3.0-4.5 584 mg/g EPAX4510TG glycerides 55 45 10 9:2 Vit E: min 3.0
443 mg/g EPAX2050TG glycerides 70 20 50 2:5 459 mg/g K85TG
glycerides 80 45.9 33.3 1.38:1 Vit E: 4.0 366 mg/g K85EE ethyl
ester 84 46 38 1.2:1 Vit E: 3.2-4.8 225 mg/g K80EE ethyl ester 81
45 36 1:0.8 Vit E: 3.2-4.8 EPAX7010EE ethyl ester 82 70 12 5.8:1
Vit E: 2.1-3.2 265 mg/g K85EE + ethyl ester + 73-76 .about.3:2 731
mg/g EPAX6000FA free fatty (2:1 w/w) acid
The solubility of CyA in various oils was found to be variable. A
blend of K85EE with EPAX6000FA increased the solubilizing power for
CyA greatly compared to either omega-3 fatty acid oil by itself.
Furthermore, this CyA solution in a mixture of K85EE and EPAX 6000
remained in the form of a clear solution at low and high
temperatures, such as 2-8.degree. C. and about 40.degree. C. No
precipitation or crystallization occurred upon cooling to
about-20.degree. C. for more than 24 hours. Thus, these initial
findings indicate that CyA microemulsion preconcentrates made with
this fish oil blend might have very good thermal stability over a
wide temperature range.
EXAMPLE 2
Preparation of Microemulsion/Emulsion Preconcentrates
To make the preconcentrate formulations, a solution containing the
poorly water soluble therapeutic agent and the oil component
containing the omega-3 fatty acid oil were prepared in appropriate
proportions by adding is the therapeutic agent in small increments
and stirring. The surfactant system was prepared by mixing
separately the chosen surfactants in their determined ratios. The
oil component/therapeutic agent solution was then combined with the
surfactant system solution to form the preconcentrate, with
stirring for approximately 5 minutes with or without heating to
30-40.degree. C. until homogeneous. Alternatively, formulations
according to the instant invention were prepared by simply
combining the given amounts of the therapeutic agent, the given
amounts of the oil component and the given amounts of the
surfactant system with stirring until a homogeneous solution was
formed. Alternatively, the therapeutic agent can be added to a
mixture of the oil component and the surfactant system and stirred
until a homogeneous solution was formed. To test the behavior of
the preconcentrates upon contact with an aqueous system, the
preconcentrate was diluted, such as 1:1, 1:10, 1:20, 1:50 or 1:100
v/v dilutions, with water to simulate conditions in the
stomach.
As given in the examples below, a variety of surfactant systems
were combined with various omega-3 fatty acid oils at varying
ratios of the components and the resulting solutions were diluted
1:20 to determine the component ratios that provide suitable
microemulsion and emulsion preconcentrate formulations. Clarity of
the resulting solutions was classified as follows: C1 denotes a
transparent solution; C2 denotes a translucent solution; C3 denotes
a slightly opaque solution; and C4 denotes a milky white solution.
Generally, the self-emulsifying microemulsion systems correspond to
the C1 to C2 solutions and the self-emulsifying emulsion systems
correspond to the C3 to C4 solutions. A pseudo-ternary phase
diagram that maps the different clarity regions for a particular
omega-3 fatty acid oil/surfactant system can be made to visualize
the appropriate ratios of the components needed to form a
microemulsion preconcentrate or an emulsion preconcentrate
formulation.
EXAMPLE 3
K85EE/Cremophor RH40/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil K85EE and a surfactant system comprising Labrasol and
Cremophor RH40 with varying percentages for all three of these
components. Table 2 charts the clarity values for this system
(placebo) upon 1 to 20 dilution with water while Table 3 charts 1
to 20 dilution clarity values for the corresponding systems in
which 25, 50, 100 and 150 mg of CyA per ml of solution were added.
From an analysis of the placebo system, it appears that the
greatest amount of oil possible in a microemulsion preconcentrate
formulation formulated according to this system is around 40-45%
K85EE.
TABLE 2 Cremophor K85EE % Labrasol % RH40 % CyA mg/ml Clarity 5 62
33 n/a C1 10 15 75 n/a C1 12 45 43 n/a C1 15 79 6 n/a C4 20 38 42
n/a C1/C2 22 65 13 n/a C4 27 20 53 n/a C1/C2 30 56 14 n/a C4 40 10
50 n/a C2 50 5 45 n/a C4 55 10 35 n/a C4
TABLE 3 Cremophor K85EE % Labrasol % RH40 % CyA mg/ml Clarity 5 62
33 25 C1 10 15 75 25 C1 12 45 43 25 C1 20 38 42 25 C1 5 62 33 50 C1
10 15 76 50 C1 12 45 43 50 C1 20 38 42 50 C1 5 62 33 100 C3 12 45
43 100 C1 20 38 42 100 C1 5 62 33 150 C4 12 45 43 150 C3 20 38 42
150 C2/C3
EXAMPLE 4
K85EE/Tween 80/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil K85EE a nd a surfactant system comprising Labrasol and
Tween 80 with varying percentages for all three of these
components. Table 4 charts the clarity values upon 1 to 20 dilution
with water for this system (placebo) while Table 5 charts the 1 to
20 dilution clarity values for corresponding systems in which 25
and 50 mg of CyA per ml of solution were added.
TABLE 4 KE85EE % Labrasol % Tween 80 % CyA mg/ml Clarity 5 62 33
n/a C1 10 15 75 n/a C1 12 45 43 n/a C1/C2 15 79 6 n/a C4 20 38 42
n/a C1/C2 22 55 13 n/a C4 27 20 53 n/a C1/C2 30 56 14 n/a C4 40 5
55 n/a C2/C3 50 5 45 n/a C2/C3 53 12 35 n/a C4
TABLE 5 K85EE % Labrasol % Tween 80% CyA mg/ml Clarity 5 62 33 25
C2 10 15 75 25 C1 12 45 43 25 C1/C2 20 38 42 25 C2 27 53 20 25 C2
40 5 55 25 C2/C3 50 5 45 25 C4 5 62 33 50 C4 10 15 75 50 C1/C2 12
45 43 50 C2/C3 20 38 42 50 C3 27 53 20 50 C2/C3
Comparison between the K85EE/Cremophor RH40/Labrasol system of
Example 3 and the K85EE/Tween 80/Labrasol system of Example 4 shows
that while the placebo systems are similar, as cyclosporin is added
to the system, the K85EE/Cremophor RH40/Labrasol system provides a
larger microemulsion region when plotted on a pseudo-ternary phase
diagram.
EXAMPLE 5
K85EE/Cremophor RH40/Tween 80/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil K85EE and a surfactant system comprising Labrasol, Tween
80 and Cremophor RH40 (holding the ratio of Cremophor RH40 to Tween
80 at 2:1) with varying percentages of K85EE, Labrasol and Tween
80/Cremophor RH40. Table 6 charts the 1 to 20 dilution clarity
values for this system (placebo) as well as the corresponding
system with 5% Ethanol included. Table 7 charts 1 to 20 dilution
clarity values for corresponding systems in which 100 mg of CyA per
ml of solution has been added.
TABLE 6 Cremophor RH40:Tween CyA K85EE % Labrasol % 80 (2:1) %
Ethanol % mg/ml Clarity 21.7 0 78.3 n/a n/a C1 21.7 12.6 66.7 n/a
n/a C1 21.7 20.8 67.5 n/a n/a C1 31 0 69 n/a n/a C1/C2 31 11 68 n/a
n/a C1/C2 31 18.4 60.6 n/a n/a C1/C2 38.8 0 61.2 n/a n/a C1/C2 38.8
9.9 51.5 n/a n/a C1/C2 38.8 16.2 48 n/a n/a C1/C2 42.5 10.5 47 n/a
n/a C1/C2 44 5 51 n/a n/a C2 48.5 0 51.3 n/a n/a C2 48.5 8.2 43.3
n/a n/a C2 48.5 13.7 37.8 n/a n/a C2 21.7 0 78.3 5% n/a C1 21.7
12.6 66.7 5% n/a C1 21.7 20.8 67.5 5% n/a C1 31 0 69 5% n/a C1/C2
31 11 68 5% n/a C1/C2 31 18.4 60.6 5% n/a C1/C2 38.8 0 61.2 5% n/a
C1/C2 38.8 9.9 51.3 5% n/a C1/C2 42.5 10 47.5 5% n/a C1/C2 44 5 51
5% n/a C1/C2 48.5 0 51.5 5% n/a C1/C2 48.5 8.2 43.3 5% n/a C2 48.5
13.7 37.8 5% n/a C2 52.5 5 42.5 5% n/a C2
Tables 6 and 7 show that inclusion of 5% ethanol compared to the
same system without ethanol provides similar microemulsion region
sizes for both placebo systems (20% to 50% oil) and the
corresponding 100 mg/ml CyA systems.
TABLE 7 Cremophor RH40:Tween CyA K85EE % Labrasol % 80 (2:1) %
Ethanol % mg/ml Clarity 42.5 10 47.5 n/a 100 C1/C2 44 6 51 n/a 100
C1/C2 46 5 49 n/a 100 C1/C2 46.5 11.5 42 n/a 100 C1/C2 47 0 53 n/a
100 C1/C2 53 8 42 n/a 100 C2/C3 42.5 10 47.5 5% 100 C1/C2 44 6 51
5% 100 C1/C2 46 5 49 5% 100 C1/C2 46.5 11.5 42 5% 100 C2 47 0 53 5%
100 C1/C2 53 8 42 5% 100 C2/C3
EXAMPLE 6
EPAX5000TG/Cremophor RH40/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil EPAX500OTG and a surfactant system comprising Labrasol and
Cremophor RH40 with varying percentages for all three of these
components. Table 8 charts the clarity values for this system
(placebo) upon 1 to 20 dilution with water as well as 1 to 20
dilution clarity values for the corresponding systems in which 25,
50, 100 and 150 mg of CyA per ml of solution were added.
TABLE 8 EPAX5000TG Cremophor % Labrasol % RH40% CyA mg/ml Clarity 5
62 33 n/a C1 10 15 75 n/a C1 12 45 43 n/a C1 15 79 6 n/a C4 20 38
42 n/a C1/C2 22 65 13 n/a C4 27 20 53 n/a C1/C2 30 56 14 n/a C4 5
62 33 25 C1 10 15 75 25 C1 12 45 43 25 C1 20 36 42 25 C1 20 27 53
25 C1 5 62 33 50 C1 10 15 75 50 C1 12 45 43 50 C1 20 36 42 50 C1 20
27 53 50 C1 5 62 33 100 C1 10 15 75 100 C1 12 45 43 100 C1 20 36 42
100 C1 20 27 53 100 C1 5 62 33 150 C3 10 15 75 150 C1 12 45 43 150
C2 20 36 42 150 C1 20 27 53 150 C1
EXAMPLE 7
EPAX6000FA/Cremophor RH40/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil EPAX6000FA and a surfactant system comprising Labrasol and
Cremophor RH40 with varying percentages for all three of these
components. Table 9 charts the clarity values for this system
(placebo) upon 1 to 20 dilution with water as well as 1 to 20
dilution clarity values for the corresponding systems in which 25,
50, 100 and 150 mg of CyA per ml of solution were added. From
analysis of the placebo system, it appears that the greatest amount
of oil possible in a microemulsion preconcentrate formulation
formulated according to this system is around 27% EPAX6000FA.
TABLE 9 EPAX6000FA Cremophor % Labrasol % RH40% CyA mg/ml Clarity 5
62 33 n/a C1 10 15 75 n/a C1/C2 12 45 43 n/a C1/C2 15 79 6 n/a C2
20 38 42 n/a C2 22 65 13 n/a C4 27 20 53 n/a C2 30 56 14 n/a C4 40
5 55 n/a C2/C3 50 5 45 n/a C4 55 10 35 n/a C4 50 20 30 n/a C4 40 32
28 n/a C4 5 62 33 25 C1 10 15 75 25 C1 12 45 43 25 C1 15 79 6 25 C4
20 38 42 25 C2 22 65 13 25 C4 27 20 53 25 C2 5 62 33 50 C1 10 15 75
50 C1 12 45 43 50 C1 15 79 6 50 C4 20 38 42 50 C1 22 65 13 50 C4 27
20 53 50 C2 5 62 33 100 C4 10 15 75 100 C1 12 45 43 100 C1 15 79 6
100 C4 20 38 42 100 C2 22 65 13 100 C4 27 20 53 100 C3 5 62 33 150
C4 10 15 75 150 C2 12 45 43 150 C3 15 79 6 150 C4 20 38 42 150 C3
22 65 13 150 C4 27 20 53 150 C3
EXAMPLE 8
K85TG/Cremophor RH40/Tween 80/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil K85TG and a surfactant system comprising Labrasol,
Cremophor RH40 and Tween 80 (with Cremophor RH40 and Tween 80 held
at a 2:1 ratio) with varying percentages for the oil, Labrasol and
the Cremophor RH40 and Tween 80 mixture. Table 10 charts the
clarity values for this system (placebo) upon 1 to 20 dilution with
water. A pseudo-ternary phase diagram showing the microemulsion
region (C1, C1/C2, and C2 clarity values) for this placebo system
upon 1 to 20 dilution is shown in FIG. 1.
TABLE 10 Cremophor RH40: Tween K85TG % Labrasol % 80 (2:1) % CyA
mg/ml Clarity 48.5 0 51.5 n/a C4 48.5 8.2 43.3 n/a C4 48.5 13.7
37.8 n/a C4 38.8 0 61.2 n/a C1/C2 38.8 9.9 51.4 n/a C3 38.8 16.2 45
n/a C4 31 0 69 n/a C2 31 11 58 n/a C2 31 16.4 50.6 n/a C4 21.7 0
78.3 n/a C1/C2 21.7 12.6 65.7 n/a C1/C2 21.7 20.8 57.5 n/a C1/C2 40
30 30 n/a C4 35 20 45 n/a C2 5 10 85 n/a C1 5 25 70 n/a C1 5 50 45
n/a C1 10 30 60 n/a C1 10 40 50 n/a C1/C2 15 10 75 n/a C1 15 15 70
n/a C2 15 60 25 n/a C1/C2 20 25 55 n/a C1/C2 25 35 40 n/a C4 25 45
30 n/a C2 35 20 45 n/a C2 40 30 30 n/a C4
Table 11 charts the 1 to 20 dilution clarity values for the
corresponding systems in which 25, 50, 100 and 150 mg of CyA per ml
of solution were added. The pseudo-ternary phase diagram given in
FIG. 2 shows the microemulsion region for the system upon 1 to 20
dilution having 100 mg/ml CyA per ml of solution.
TABLE 11 Cremophor RH40: Tween K85TG % Labrasol % 80 (2:1) % CyA
mg/ml Clarity 21.7 0 78.3 100 C1 21.7 12.6 65.7 100 C1 21.7 20.8
57.5 100 C1/C2 31 0 69 100 C1/C2 31 11 58 100 C2 31 16.4 50.6 100
C2/C3 38.8 0 61.2 100 C1/C2 38.8 9.9 51.4 100 C2/C3 38.8 16.2 45
100 C3 48.5 0 51.5 100 C3 48.5 8.2 43.3 100 C3 48.5 13.7 37.8 100
C4
EXAMPLE 9
K85TG/Cremophor RH40/Labrasol
Samples were prepared according to Example 2 for the omega-3 fatty
acid oil K85TG and a surfactant system comprising Labrasol and
Cremophor RH40 with varying percentages for all three of these
components. Table 12 charts the clarity values for this system
(placebo) upon 1 to 20 dilution with water as well as 1 to 20
dilution clarity values for the corresponding systems in which 25,
50, 100 and 150 mg of CyA per ml of solution were added. From an
analysis of the placebo system, it appears that the greatest amount
of oil possible in a microemulsion preconcentrate formulation
formulated according to this system is around 27% K85TG.
The microemulsion region on a pseudo-ternary phase diagram obtained
by plotting the data for the K85EE/Cremophor/Labrasol system
provided in this example is similar to that for the corresponding
EPAX5000TG system (Example 6) and the EPAX6000FA system (Example 7)
over a range of 0 to 150 mg/ml CyA. The corresponding K85EE system
(Example 3) appears to form a larger microemulsion region than the
K85TG system.
TABLE 12 Cremophor K85TG % Labrasol % RH40% CyA mg/ml Clarity 5 62
33 n/a C1/C2 10 15 75 n/a C1 12 45 43 n/a C1 15 79 6 n/a C4 20 38
42 n/a C2/C3 22 65 13 n/a C4 27 20 53 n/a C2 30 56 14 n/a C4 5 62
33 25 C1 10 15 75 25 C1 12 45 43 25 C1 20 38 42 25 C2 20 27 53 25
C1 5 62 33 50 C1 10 15 75 50 C1 12 45 43 50 C1 20 38 42 50 C2 20 27
53 50 C1 5 62 33 100 C1 10 15 75 100 C1 12 45 43 100 C1 20 38 42
100 C2 20 27 53 100 C1 5 62 33 150 C2 12 45 43 150 C3 20 38 42 150
C3 27 20 53 150 C1
EXAMPLE 10
Mixed Fish Oils/Cremophor RH40/Tween 80/Labrasol
Samples were prepared according to Example 2 for the systems
containing a mixture of K85EE and EPAX6000FA and a surfactant
system comprising Labrasol, Tween 80 and Cremophor RH40 with
varying percentages as described in Table 13. Table 13 charts the
clarity values for these systems (placebo) upon 1 to 20 dilution
with water as well as 1 to 20 dilution clarity values for the
corresponding systems in which 50 or 100 mg of CyA per ml of
solution were added.
TABLE 13 Clarity Clarity Clarity Labrasol (without (with 100 (with
50 % CyA) mg CyA) mg CyA) K85EE/ Cremophor EPAX6000F RH40/ A Tween
80 (2.5:1) % (2:1) % 21.7 65.7 12.6 C1 C1 C1 31 58 11 C1 C1 C1 38.8
61.2 0 C1/C2 C1/C2 C2 38.8 51.4 9.9 C1/C2 C1/C2 C1/C2 38.8 45 16.2
C1/C2 C1/C2 C1/C2 48.5 51.5 0 C2 C2 C3 48.5 43.3 8.2 C2 C2 C2/C3
48.5 37.8 13.7 C2 C2 C2/C3 50.9 49.1 0 C3 C3 C3 K85EE/ Cremophor
EPAX6000F RH40/ A Tween 80 (5:1) % (4:1) % 40 55 5 C2 C1/C2 C1 42.5
52.5 5 C1/C2 C1/C2 C1 45 50 5 C1/C2 C1/C2 C1 47 48 5 C2 C2 C1/C2
K85EE/ Cremophor EPAX6000F RH40/ A Tween 80 (5:1) % (2:1) % 40 55 5
C1/C2 C1/C2 C1/C2 42.5 52.5 5 C2 C1/C2 C1/C2 45 50 5 C2 C1/C2 C2 47
48 5 C2 C2 C2
EXAMPLE 11
Formulations
The following microemulsion preconcentrate formulations according
to the instant invention were prepared as follows. The given
amounts of cyclosporin, the given amounts of the oil containing
omega-3 fatty acid oil, and the given amounts of the surfactant
system were stirred until a homogeneous solution was formed. The
resulting cyclosporin-containing composition was transferred to a
machine for preparing soft capsules and then encapsulated according
to conventional methods for producing soft capsules. These products
were designed for daily administration, for example administration
of 3-8 capsules daily, thus providing both a therapeutically
effective amount of the therapeutic agent cyclosporin A (300-800 mg
for Formulations 1 and 2 or 75-200 mg cyclosporin A for Formulation
3) and a pharmaceutically effective amount of an omega-3 fatty acid
oil (1.03-2.74 g EPA+DHA for Formulations 1 and 3 or 1.39-3.70 g
EPA+DHA for Formulation 2) per day. Formulation 4 contains a
mixture of omega-3 fatty acid oils as well as minor amounts of a
hydrophilic solvent system. Of course, a daily dose may contain
combinations of capsules having differing therapeutic agent and/or
omega-3 fatty acid oil amounts such as the capsules of Formulations
1, 2, 3 and 4.
% (wt) of placebo Component system wt/capsule Formulation 1 Oil
Component: K85EE 37% 407 mg (343 mg EPA + DHA) Surfactant system:
Cremophor RH40 and 53% 583 mg Tween 80 (2:1) Labrasol 10% 110 mg
Cyclosporin A 100 mg 1200 mg total Formulation 2 Oil Component:
K85EE 50% 550 mg (462 mg EPA + DHA) Surfactant system: Cremophor
RH40 and 40% 440 mg Tween 80 (2:1) Labrasol 10% 110 mg Cyclosporin
A 100 mg 1200 mg total
Formulation 3 % (wt) of placebo Component system wt/capsule Oil
Component: K85EE 37% 407 mg (343 mg EPA + DHA) Surfactant system:
Cremophor RH40 and 53% 583 mg Tween 80 (2:1) Labrasol 10% 110 mg
Cyclosporin A 25 mg 1125 mg total
Formulation 3 % (wt) of placebo Component system wt/capsule Oil
Component: K85EE 37% 407 mg (343 mg EPA + DHA) Surfactant system:
Cremophor RH40 and 53% 583 mg Tween 80 (2:1) Labrasol 10% 110 mg
Cyclosporin A 25 mg 1125 mg total
Additional microemulsion preconcentrate formulations according to
the instant invention were also prepared as given below in Table
14. The amount of Cyclosporin A present is given as mg per 1.1 of
the preconcentrate (placebo) and the amount of the other components
are given as a weight percentage of the preconcentrate
(placebo).
TABLE 14 Formulation No. 5 6 7 8 9 10 11 12 Cyclosporin 25 25 25
100 25 100 25 100 A K85EE 37 K80EE 37 37 37 37 37 37 37 Cremophor
35.33 35.33 38.67 35.33 38.7 38.7 35.3 35.3 RH40 Tween 80 17.67
17.67 19.33 17.67 19.3 19.3 17.7 17.7 Labrasol 10 5 5 Imwitor 375 5
5 5 5 Ethanol 5 5 5 5 5
EXAMPLE 12
Formulations Containing Hydrophilic Solvent Systems
Preconcentrate formulations containing omega-3 fatty acid oil, a
surfactant system and more than minor amounts of a hydrophilic
solvent system are specified in Table 15. Clarity values for 1 to
50 dilutions of these formulations in a mixture of water and
simulated gastric fluid (1:1) are given in Table 15.
TABLE 15 Formulation 13 Formulation 14 Formulation 15 Formulation
16 mg/cap % mg/cap % mg/cap % mg/cap % Therapeutic Agent 7.0% 7.8%
7.6% 7.4% Cyclosporin A 50 50 50 50 Oil Component 21.1% 23.3% 22.9%
22.1% EPAX6000FA 50 50 50 50 K85EE 100 100 K85TG 100 100 Surfactant
System 51.5% 51.1% 50.4% 48.5% Labrasol 90 75 75 100 Myrj-52 130
100 100 75 Tween 80 75 80 80 80 Vitamin E-TPGS 70 75 75 75
Hydrophilic Solvent 20.4% 17.8% 19.1% 22.1% System Ethanol 50 40 50
50 1,2 Propylene Glycol 95 75 75 100 Clarity C1 C1 C2 C2
Additional preconcentrate formulations containing omega-3 fatty
acid oil, a surfactant system and more than minor amounts of a
hydrophilic solvent system are given below as Formulations 17 and
18.
Formulation 17 Component % (wt) of system wt/capsule Oil component:
K85EE 5.9% 50 mg EPAX6000FA 11.8% 100 mg Surfactant system: Tween
20 27.9% 237.5 mg Tween 80 27.9% 237.5 mg Hydrophilic Solvent
System Ethanolic NaOH (800 20.6%* 175 mg mg NaOH in 12 ml EtOH)
Cyclosporin A 5.9% 50 mg 850 mg total *0.3% EtOH
Formulation 18 Component % (wt) of system wt/capsule Oil component:
EPAX5000TG 8.3% 100 mg EPAX6000FA 16.5% 50 mg Surfactant system:
Tween80 12.0% 72.7 mg Glycerox 767 19.2% 116.4 mg Vitamin E-TPGS
12.8% 77.3 mg Hydrophilic Solvent System Ethanol 11.7% 70.9 mg
Ethanolic NaOH (66.7 11.3% 68.2 mg mg NaOH in 1 ml EtOH)
Cyclosporin A 8.3% 50 mg 605.5 mg
Formulations containing fenofibrate, a potent lipid modulator
agent, were prepared by mixing the omega-3 fatty acid oil component
with the drug powder followed by the addition of the surfactant
system and hydrophilic solvent system. The compositions may be
prepared at room temperature or heated to 40-50.degree. C. to
accelerate the solubilization process. Several mixing techniques
can be used ranging from mechanical stirring and agitation to
sonication. The fenofibrate composition shown below provides a
liquid or semi-solid preconcentrate at room temperature.
In vitro testing of the preconcentrates was carried out by diluting
the preconcentrate in 50-100 fold water or simulated gastric fluid
with gentle mixing or shaking. The aqueous medium temperature
varied between 20 and 37.degree. C. Particle size analysis was then
carried out using a Nicomp 370. Data reported for Formulation 19
below corresponds to volume weighted distributions.
Formulation 19 Component Quantity (mg) Oil component: EPAX4510 TG
189 EPAX6000 FA 95 Surfactant system: Tween 80 136 Myrj 52 236
Vitamin E-TPGS 164 Labrasol 127 Hydrophilic Solvent System Ethanol
91 1,2-propylene glycol 182 Fenofibrate (mean particie size: 20 nm)
100
EXAMPLE 13
Evaluation of Oral Bioavailability
A two period, two treatment randomised crossover study was
designed. Ten (10) healthy male volunteers were recruited into the
study and the following treatments were administered during the
study: Formulation 5 (25 mg Cyclosporine) and Neoral.RTM.
(Novartis) (25 mg Cyclosporine). Both treatments were dosed as four
25 mg capsules giving a total dose of 100 mg cyclosporine. Nine (9)
subjects successfully completed both treatment periods of this
study. Table 16 summarises the mean primary pharmacokinetic
parameters for the two treatments.
The results of this study showed that the microemulsion Formulation
5 had a relative bioavailability of 0.81 compared to Neoral.RTM.
with significantly lower peak cyclosporine blood concentrations.
Visual inspection of the individual plots suggested that the
initial rate of cyclosporine absorption was slower following
administration of the omega-3 oil product.
TABLE 16 Parameter Formulations 5 Neoral capsules Cmax (ng/ml)
392.76 .+-. 95.93 489.21 .+-. 98.08 90% Cl vs Neoral 66-91
AUC.sub.(0-t) (ng/ml .multidot. hr) 1083.44 .+-. 300.95 1346.92
.+-. 256.53 90% Cl vs Neoral 72-86 AUC.sub.(0-infinity) (ng/ml
.multidot. hr) 1115.54 .+-. 302.74 1385.91 .+-. 244.50 90% Cl vs
Neoral 72-86 F ratio 0.81 .+-. 0.16
The combination of reduced peak blood concentrations along with the
inclusion of the omega-3 oil in the microemulsion formulation may
result in a reduction of the nephrotoxic side effects of
cyclosporine. The relative bioavailability of approximately 80% of
Neoral.RTM. for this formulation is considerably higher than that
reported for the Sandimmun.RTM. cyclosporine formulation.
Stability evaluations were undertaken for Formulation 5 at
25.degree. C. and 60% relative humidity as well as 40.degree. C.
and 75% relative humidity. No crystallization occurred under either
of these conditions for Formulation 5 through 14 weeks. Upon
dilution of the these preconcentrates, the clarity of the resulting
microemulsions remained C1/C2.
A second biostudy was undertaken to evaluate the oral
bioavailability of Formulations 6, 7 and 8 compared to Neoral Oral
Solution (100 mg). The formulations were packaged in vials and
diluted with orange juice prior administration Ten human subjects
completed the study which consisted of four treatment periods.
Table 17 summarises the primary PK parameters for each of the four
products administered during the study.
TABLE 17 Formulation Formulation Formulation Neoral Parameter 6 7 8
Solution Cmax 313.86 .+-. 312.86 .+-. 335.97 .+-. 472.31 .+-.
(ng/ml) 68.96 73.25 47.38 89.00 AUC.sub.(0-24 h) 1063.30 .+-.
1042.96 .+-. 1068.85 .+-. 1523.20 .+-. (ng/ml .multidot. hr) 301.27
306.84 258.50 313.73 AUC.sub.(0-infinity) 1123.61 .+-. 1111.52 .+-.
1121.44 .+-. 1595.80 .+-. (ng/ml .multidot. hr) 323.66 333.47
276.67 335.58 F ratio* 71.3 .+-. 19.1 70.2 .+-. 17.9 72.1 .+-. 21.5
*based on AUC.sub.(0-infinity) data
All three products showed very similar bioavailabilities relative
to Neoral Solution, approximately 71%. These three products
produced good microemulsions of C1/C2 clarity on dilution 1 in 20
with deionized water. The mean particle size of these
microemulsions was determined to be 38.7.+-.0.3 nm, 39.1.+-.0.1 nm
and 39.1.+-.0.4 nm (intensity weighted) for Formulation 6, 7 and 8,
respectively.
* * * * *